JP2009529545A - Para-substituted 2-alkoxyphenol compounds - Google Patents

Abstract

式中、Ｒ^１は、メチルまたはエチルであり；Ｙは、ＮＨ、ＯまたはＳであり；Ｒ^２およびＲ^３は、互いに独立して水素またはＣ_１〜３アルコキシであり；ｎは、０または１であり；またＣ−２とＣ−２’との間の点線は、結合なし、単結合または−（ＣＨ_２）_ｍ−基の少なくとも１つを表し、ここでｍは１または２である、
で表される、パラ置換２−アルコキシフェノール類。これらの製造方法およびこれらを有するかまたは用いる消費者製品もまた、開示する。With cooling properties, formula (I)

In which R ¹ is methyl or ethyl; Y is NH, O or S; R ² and R ³ independently of one another are hydrogen or C _1-3 alkoxy; n is 0 or And the dotted line between C-2 and C-2 ′ represents at least one of no bond, a single bond or a — (CH ₂ ) _m — group, where m is 1 or 2. ,
Para-substituted 2-alkoxyphenols represented by: These manufacturing methods and consumer products having or using them are also disclosed.

Description

  The present invention relates to para-substituted 2-alkoxyphenols having cooling properties. The invention further refers to these manufacturing methods and consumer products containing them.

  In the flavor and fragrance industry, it has a unique cooling property that gives the user a comfortable cooling effect, and it is a continuous product for a variety of products, especially ingestible and suitable for use in topical products. There is a request.

  Cooling compounds, i.e. compounds that provide a cooling sensation to the body's skin or mucous membranes, are well known in the art and are used in various products such as foodstuffs, tobacco products, beverages, chewing gums, dentifrices, mouthwashes and toiletries. Has been used extensively.

  The most well known compound is l-menthol, which is found naturally in mint oil. Because menthol has a strong mint-like odor and bitterness and gives a burning sensation when used at high concentrations, various other menthyl ester-based and menthylcarboxamide-based cooling compounds have been developed. ing. One that has enjoyed significant success is N-ethyl p-menthane-carboxamide (WS-3), which is therefore also frequently used as a standard.

Surprisingly, it has been found that certain 2-alkoxyphenol derivatives are more potent than l-menthol and still have a stronger cooling strength than WS-3. Accordingly, in one embodiment, at least one of the subject compounds is used as a coolant, wherein the compound is of formula (I)

Where
R ¹ is methyl or ethyl;
Y is NH, O or S;
R ² and R ³ are independently selected from hydrogen or at least one of C _1-3 alkoxy, such as methoxy, ethoxy or iso-propoxy;
n is 0 or 1; and the dotted line between C-2 and C-2 ′ represents no bond, a single bond or at least one of the — (CH ₂ ) _m — group, where m is 1 or 2,
It is represented by

Non-limiting examples include R ² attached at C-4, R ³ attached at C-4 ′, or R ² and R ³ attached at C-4 and C-4 ′, respectively. It is a compound represented by the formula (I). Non-limiting examples also include compounds of formula (I) wherein R ² and R ³ have the same chemical formula.

  In particular, embodiments include 4-((benzhydrylamino) methyl) -2-methoxyphenol, 4-((bis (4-methoxyphenyl) -methylamino) -methyl) -2-methoxyphenol, 4-(( 1,2-diphenylethylamino) methyl) -2-methoxyphenol, 4-((benzhydryloxy) methyl) -2-methoxyphenol, 4-((9H-fluoren-9-ylamino) methyl) -2- It is a compound represented by the formula (I) including at least one of methoxyphenol or 4-((benzhydrylamino) methyl) -2-ethoxyphenol.

  The compound represented by the formula (I) can be used in a mucosa such as an oral mucosa or a product applied to the skin to impart a cooling feeling. By “application” is meant contacting in all forms, eg ingestion, topical application or inhalation in the case of tobacco products. In the case of application to the skin, this may be due, for example, to the inclusion of the compound in a cream or ointment or in a sprayable composition. Accordingly, there is also provided a method for imparting a cooling effect to mucous membranes or skin by applying a product containing an effective amount of the above-mentioned compound to the site.

  Products applied to the oral mucosa include foods and beverages introduced into the mouth and swallowed, as well as products taken for reasons other than their nutritional value, such as tablets, mouthwashes, throat sprays, dentifrices and chewing gum. May be included. The product applied to the skin may be selected from perfumes, toiletries, lotions, oils and ointments that can be applied to the skin of the human body for medical reasons as well as for other reasons. Accordingly, in a further aspect, the composition is represented by at least one formula (I) in an amount sufficient to stimulate cold receptors in the area of skin or mucous membrane that contacts and thereby promotes the desired cooling effect. A composition comprising the compound is provided. A cooling effect is achieved by applying a product comprising a compound of formula (I) of less than 5000 ppm, in a particular embodiment 50-3000 ppm, for example about 500 ppm, for example a mouthwash or chewing gum to the mucosa, for example the oral mucosa. can do. When used for beverages, the addition of about 15 ppm may be sufficient to achieve a cooling effect.

  Specific examples of food products and beverages include alcoholic or non-alcoholic beverages such as fruit juices, fruit liquor, milk beverages, carbonated beverages, soft drinks and health and nutritional drinks; frozen confectionery such as ice cream Desserts such as jelly and pudding; confectionery such as cakes, cookies, chocolate and chewing gum; jams; candy; bread; teas such as green tea, black tea, chamomile tea, mulberry leaf tea, rooibos tea, peppermint tea; Seasonings; instant beverages; snack foods and the like may be included, but are not limited to these.

  Other examples of topical products include skin care cosmetics such as cleansing tissue paper, talcum powder, facial creams, lotions, tonics and gels, hand creams, hand and body lotions, anti-fat deposition / slimming creams and lotions, lotions Sunscreen lotions, balms, gels, sprays and creams; sunscreen cosmetics including sunscreen lotions, balms, gels, sprays and creams; after sun lotions, sprays and creams; soaps, toothpicks, lipsticks, bathing agents, Deodorants and antiperspirants, facial cleansing creams, massage creams and the like may be included, but are not limited to these.

  Therefore, it is further selected from at least one of products applied to the oral mucosa or products applied to the skin, such as topical products, oral care products, nasal care products, toiletries, ingestible products and chewing gum etc. A final product is provided, the final product comprising a product base and an effective amount of at least one cooling compound of formula (I) as defined above.

  The above compounds may be used alone or other cooling compounds known in the art, such as menthol, menthone, isopulegol, N-ethyl p-menthane carboxamide (WS-3), N, 2,3-trimethyl-2 -Isopropylbutanamide (WS-23), menthyl lactate, menthose glycerin acetal (Frescolat® MGA), mono-menthyl succinate (Physcool®), mono-menthyl glutarate, O-menthyl glycerol (CoolAct (Registered trademark) 10) and 2-sec-butylcyclohexanone (Freskomenthe (registered trademark)), menthane, camphor, pregol, cineol, mint oil, peppermint oil, spearmint oil, eucalyptus oil, 3-l-menthoxypropane-1 , 2-diol, 3-l-menthoxy-2-methylpro 1,2-diol, p-menthane-3,8-diol, 2-l-menthoxyethan-1-ol, 3-l-menthoxypropan-1-ol and 4-l-menthoxybutane- It may be used in combination with 1-ol. Further examples of cooling compounds can be found, for example, in WO 2005/049553, which is introduced by reference.

  Cooling compounds may be used in the product, simply by mixing the compound directly with the product, or they may be incorporated at a relatively early stage into entrapment materials such as polymers, capsules, microcapsules and nanocapsules, liposomes. May be incorporated with film-forming agents, absorbents, such as cyclic oligosaccharides, or they may be chemically conjugated to a substrate, which is then applied to the cooling compound by applying external stimuli such as temperature, enzymes, etc. It may be adapted for release and then mixed with the product. Or using alcohols or polyhydric alcohols such as glycerin, propylene glycol, triacetin and migliol, natural rubber such as gum arabic, or surfactants such as glycerin fatty acid esters and monosaccharide fatty acid esters. And may be added during solubilization, dispersion or dilution.

  The above groups of compounds are not described in the literature and are therefore independently novel.

式中、
Ｒ^１は、メチルまたはエチルであり；
Ｙは、ＮＨ、ＯまたはＳであり；
Ｒ^２およびＲ^３は、独立して水素またはＣ_１〜３アルコキシ、例えばメトキシ、エトキシまたはイソ−プロポキシの少なくとも１つから選択され；
ｎは、０または１であり；また
Ｃ−２とＣ−２’との間の点線は、結合なし、単結合または−（ＣＨ_２）_ｍ−基の少なくとも１つを表し、ここでｍは１または２である、
で表される化合物に言及する。 Thus, the embodiment further comprises formula (I)

Where
R ¹ is methyl or ethyl;
Y is NH, O or S;
R ² and R ³ are independently selected from hydrogen or at least one of C _1-3 alkoxy, such as methoxy, ethoxy or iso-propoxy;
n is 0 or 1; and the dotted line between C-2 and C-2 ′ represents no bond, a single bond or at least one of the — (CH ₂ ) _m — group, where m is 1 or 2,
Is referred to.

  The compound of formula (I) where Y is NH is reacted with the appropriate diphenylmethanamine with the appropriate 3-alkoxy-4-hydroxy-benzaldehyde to give the corresponding imine, which is then further reduced. It can be prepared by obtaining a secondary amine.

  A compound of formula (I) where Y is O can be prepared by reacting a suitable diphenylmethanol with a suitable 4- (hydroxymethyl) -2-alkoxyphenol.

  A compound of formula (I) wherein Y is S can be prepared by alkylating a suitable protected 4- (mercaptomethyl) -2-methoxyphenol with a suitable diphenylmethyl halide. it can.

  The compositions and methods will now be further described with reference to the following non-limiting examples. It is understood that these examples are for illustrative purposes only, and that changes and modifications can be made by those skilled in the art. It should be understood that the described aspects are not only in the alternative, but can also be combined.

Example 1: 4-((Benzhydrylamino) methyl) -2-methoxyphenol A) 4-((E) (Benzhydrylimino) methyl) -2-methoxyphenol A magnetic stirrer and Dean and Stark trap were installed In a 250 mL flask (under N ₂ ), 10.0 g diphenylmethanamine and 8.3 g vanillin are dissolved in 150 mL hexane and the mixture is heated at reflux for 3 hours. At the end of the reaction, approximately 1 mL of water was captured by the Dean and Strak apparatus. The mixture was oiled out at low temperature and the residue was recrystallized from MTBE / hexanes to give 8.32 g of yellowish crystals. The mother liquor was further crystallized to obtain 4.9 g of white crystals of the second crop, for a total yield of 76%.

B) 4-((Benzhydrylamino) methyl) -2-methoxyphenol In a 250 mL flask equipped with a magnetic stirrer (under N ₂ ), 8.3 g of 4-((benzhydrylimino) -methyl ) -2-Methoxyphenol was dissolved in 150 mL of methanol, 1.7 g of sodium borohydride was added, and the mixture was stirred overnight at room temperature.
The orange solution was concentrated and partitioned twice between MTBE and brine. The organic layer was washed with brine, dried over MgSO ₄ and concentrated. The residue was recrystallized in MTBE to obtain 7.80 g of white crystals having a melting point of 115-118 ° C. (yield 93%)

Example 2: 4-((Bis (4-methoxyphenyl) methylamino) methyl) -2-methoxyphenol The procedure outlined in Examples 1 and 2 was repeated with bis (4-methoxyphenyl) -methylamine. -((Bis (4-methoxyphenyl) methylamino) methyl) -2-methoxyphenol is obtained.

Example 3: 4-((1,2-Diphenylethylamino) methyl) -2-methoxyphenol The procedure outlined in Example 1 was repeated with 1,2-diphenylethanamine to give 4-((1,2- Diphenylethylamino) methyl) -2-methoxyphenol is obtained.

Example 4: 4-((Benzhydryloxy) methyl) -2-methoxyphenol In a 500 mL flask equipped with a magnetic stirrer (under N ₂ ), 9.21 g benzhydrol, 7.70 g bunnies Lil alcohol and 27.91 g ceric ammonium nitrate are dissolved in 100 mL acetonitrile. The mixture is stirred at reflux for 4 hours. The reaction mixture was partitioned between MTBE and water. The organic layer was washed with water and brine, dried over MgSO ₄ , concentrated and purified by column chromatography to give 1.2 g of colorless oil (yield 7.5%).

Example 5: 4-((9H-Fluoren-9-ylamino) methyl) -2-methoxyphenol The procedure outlined in Example 1 was repeated with 9H-fluoren-9-amine and vanillin to give 4-((9H- Fluoren-9-ylamino) methyl) -2-methoxyphenol (melting point: 148-150 ° C.) is obtained.

Example 6: 4-((Benzhydrylamino) methyl) -2-ethoxyphenol The procedure outlined in Example 1 was repeated with 3-ethoxy-4-hydroxybenzaldehyde to give 4-((benzhydrylamino) methyl. ) -2-Ethoxyphenol (melting point: 89-91 ° C.) is obtained.

Example 7: Cooling strength A small group of panelists tasted various aqueous solutions of the compound of formula (I), and either solution was similar to or slightly higher than the menthol solution at 2 ppm. Asked to show if they have strength. The results are shown in Table 1.

  As is apparent from the above results, the compounds of the present invention are at least twice as potent as 1-menthol and more potent than WS-3.

Example 8: Application in toothpaste

  The chemicals are mixed in a dentifrice gel, a piece of dentifrice gel is placed on a toothbrush and the panelist's teeth are brushed. Wash mouth with water and exhale. A strong cooling sensation is felt by panelists in all areas of the mouth with a slight bitter taste. The cooling perception continues for 45 minutes.

Claims (5)

Formula (I)

Where
R ¹ is methyl or ethyl;
Y is NH, O or S;
R ² and R ³ are independently selected from hydrogen or at least one of C _1-3 alkoxy;
n is 0 or 1; and the dotted line between C-2 and C-2 ′ represents no bond, a single bond or at least one of the — (CH ₂ ) _m — group, where m is 1 or 2,
A compound represented by 4-((benzhydrylamino) methyl) -2-methoxyphenol,
4-((bis (4-methoxyphenyl) -methylamino) -methyl) -2-methoxyphenol,
4-((1,2-diphenylethylamino) methyl) -2-methoxyphenol,
4-((benzhydryloxy) methyl) -2-methoxyphenol,
The compound of claim 1, comprising at least one of 4-((9H-fluoren-9-ylamino) methyl) -2-methoxyphenol or 4-((benzhydrylamino) methyl) -2-ethoxyphenol. .   Use of a compound of formula (I) as defined in claim 1 or 2 as a coolant.   A method for imparting a cooling effect to the mouth or skin, wherein the method comprises applying a product containing the compound represented by formula (I) defined in claim 1 or 2 to the site.   A product selected from at least one of a product applied to the oral mucosa or a product applied to the skin, wherein the product is a product base and an effective amount of the formula (I The said product containing the cooling compound represented by this.